Despite remarkable advances in HIV medication effectiveness, adherence to treatment recommendations among HIV-infected youth is alarmingly poor, resulting in preventable morbidity and mortality. Most current HIV treatment adherence interventions are designed to change thoughts and behaviors, but have limited effect on improving HIV medication adherence. Successful medication adherence relies on individuals' on-going self-regulation, an intertwined process involving coping, psychological function, and cognitive function. In this application, we propose to study the ability of mindfulness-based stress reduction (MBSR) to improve HIV-infected youth's HIV medication adherence and self-regulation. MBSR is a program of meditation techniques to enhance participants' mindfulness, or present-focused, non-judgmental awareness. Our previous research in urban youth shows that MBSR improves health-related behaviors and self-regulation. Further, preliminary data from our R21 on MBSR for stress-reduction in HIV-infected youth suggest an association between mindfulness and improved medication adherence, as well as enhanced self-regulatory processes (coping, psychological function, and cognitive function). This intervention is innovative and significant because it focuses on self-regulatory processes, and it may be used alone or as a complement to current interventions addressing specific behaviors. Building on the promising, but preliminary, findings of our R21 pilot study, this RCT will determine the effect of MBSR on HIV medication adherence (Aim 1) and self-regulation (Aim 2) among HIV-infected youth. To achieve these aims, our experienced, collaborative team will conduct a full-scale, two-site RCT with 162 HIV-infected youth 13-24 years old, comparing 1) MBSR, 2) an active control (health education program), and 3) usual care. We will determine whether group assignment predicts outcomes of interest. We will also explore: 1) associations (and potential mediation) among mindfulness, self-regulation, and medication adherence and 2) using qualitative methods, reasons for non/low-participation to inform future implementation planning. While medication adherence is our primary adherence outcome, we will also look at other HIV treatment behaviors of appointment-keeping and sex behavior. Additionally, we will employ an innovative approach to use 2 potentially-complementary methods of medication adherence data collection.